CTS 2024: Considering structural and functional biomarkers in dry AMD

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Eleonora Lad, MD, PhD, discusses the stages of dry AMD from early to intermediate to geographic atrophy, while also assessing which endpoints are most useful for these different stages.

Eleonora Lad, MD, PhD, sat down with Modern Retina to discuss the role of structural and functional biomarkers in dry AMD treatment as well as the future of clinical trials. She presented at the Clinical Trials at the Summit conference on June 8, 2024, in Park City, Utah. Lad shares some key takeaways here with Group Editorial Director Sheryl Stevenson.

Video Transcript

Editor’s note - The following transcript has been lightly edited for clarity.

Sheryl Stevenson: We are joined today by Dr. Eleonora Lad, who is among the presenters at this year's Clinical Trials at the Summit. So delighted to see you! Looking forward to your talk. You will be presenting on dry AMD regarding structural and functional biomarkers. What can you tell us about your talk?

Eleonora Lad, MD, PhD: Thanks so much. It's an honor to be here and be interviewed today. I guess I'll start with some take-home points and then I'll go through the salient details that I want to take away from this.

So briefly, this talk is about the stages of dry AMD from early to intermediate to geographic atrophy [GA], which is the late stage of AMD and the only one for which there are currently available FDA treatments — 2 in number since last year. We are assessing which endpoints are most useful for these different stages. For early and intermediate AMD, there's certainly value in dark adaptation testing, microperimetry, and structure-function correlation analyses. GA is different and that's why so many trials have failed so far, because best-corrected visual acuity is not the best endpoint, which is why we use structural endpoints like fundus autofluorescence. But there are elements to BCVA that are useful for geographic atrophy. So we now understand from natural history trials and Proxima and lampalizumab studies that higher best-corrected visual acuity loss is in the better eye, not the worst eye that is typically enrolled in the therapeutic studies. Eyes with better starting acuity also have higher BCVA loss, so more opportunity to change, also smaller lesions that are unifocal, and also the presence of reticular pseudodrusen or subretinal drusenoid deposits is also a marker of higher BCVA loss. So had we enrolled those patients in the therapeutic studies of complement inhibitors in the past year we would have seen perhaps a BCVA loss in the prespecified analyses. That's what we gleaned from natural history data so far.

Reading speed has a more acute slope or decline than BCVA so holds more promise. Low luminance visual acuity is also promising and there are complex relationships between GA lesions and BCVA and also microperimetry. The analysis of the perilesional points at the edge of GA is a good marker of disease activity and is likely to show a change with newer protocols. Now, there are some post-hoc analysis of the GA phase 3 anti-complement trials, and prespecified analysis of the recent phase 2 trial of the C1q inhibitor that have revealed functional benefits in best-corrected visual acuity, low luminance visual acuity, and microperimetry in the perilesional area. So those are finally panning out.

And just to highlight the future trials of dry AMD can use all these prior data and knowledge to define subgroups of GA-affected eyes that have high risk of both anatomic expansion for the primary endpoint if you want it to be GA area or concomitant functional loss. So we'll be able to construct better studies in the future with our current knowledge to design better studies for both structural and functional assessments.

Stevenson: Thank you for that summation. So what might be the next steps in this research?

Lad: The next step is to probably get a paper out, a detailed analysis on all these biomarkers, structural and functional, in geographic atrophy in earlier stage of disease...move treatments in earlier stages. Right now, many industry sponsors are addressing extrafoveal lesions that are farther out than prior studies. They're limiting lesion size so we can pick up the functional deficit better. In the end, what we'll need to do is address the intermediate stage of disease. We'll need to have better trial designed for intermediate AMD. I think there's definitely value in the ellipsoid zone area as a structural biomarker that could be primary with a functional surrogate that could be dark adaptation with the modified protocol.

And we can use other functional tests as well with newer technology like virtual reality [VR] goggles. We will use a lot of information from our glaucoma colleagues where they do multiple repeated testing over time using VR goggles. We can get more tests done at home, etc, or in a clinic setting so that we can lower that margin of error of each test to show efficacy to regulatory agencies like FDA and EMA [European Medicines Agency]. A lot of good work to be done but we want to design better studies and move the treatment to earlier stages is the bottom line.

Stevenson: That's fascinating. And speaking more about research, what advice would you give to researchers and clinicians about dry AMD?

Lad: To start imaging the patients robustly using high-resolution OCT with ideally 97 line scan. So it can get as much information for future AI analyses and efforts on ellipsoid zone, attenuation, partial, total, or total easy loss depending on terminology....all the biomarkers of interest, and also....the drusen characteristics are very important. And also autofluorescence because they want to understand more about the patterns of GA as they expand over time.

And then work with colleagues that like to do functional testing. I know that's not easy to implement in a busy clinical practice, but maybe partner with researchers or optometrists and do some dark adaptation at some point and learn more how to do it correctly and microperimetry because I think it'll become useful for us.

Stevenson: Any additional thoughts or key takeaways you'd like to share about the future of dry AMD and clinical trials?

Lad: I think the future of dry AMD is extremely bright. We have an explosive pipeline currently with multiple mechanism of actions. I think many of them are very promising. They range from drugs, devices, to drug-device combinations so the future I think is really bright. I tell my patients in clinic this every day, and it gives them a lot of hope.

In addition to the first 2 FDA approvals that started the field of therapeutics in advanced dry AMD, I think there'll be a lot more room for prevention of vision loss and even improving vision if these drugs work well or devices. So a bright future ahead for the treatment of dry AMD and a lot of meaningful work that needs to be done in the space.

Stevenson: Thank you so much. It certainly is a fascinating time to be an ophthalmology and we really appreciate your time today.

Lad: Thank you so much for your interest. The pleasure is mine.

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